Discovery of Limonoids from Xylocarpus granatum as Potential Leads against Neuroinflammation

Discovery of new natural products with both anti-inflammatory effects on activated microglia and protective activity on dopaminergic neurons is a new strategy to find new drug leads against neuroinflammation in Parkinson's disease. In this work, nine new limonoids, named thaigranatumins A-I (1-9), and two new protolimonoids, named thaigranatumins J (10) and K (11), were obtained from seeds of the Thai mangrove, Xylocarpus granatum. The structures of these compounds were established by analysis of spectroscopic data, single-crystal X-ray diffraction (Cu Kα), and comparison of experimental and calculated ECD spectra. Thaigranatumin A (1), containing a C-16/C-30 δ-lactone ring-D and a tetra-substituted C8-O-C17-bridged tetrahydrofuran ring-F, is the first limonoid featuring a unique 6/6/6/6/6/5/5-fused heptacyclic framework. Thaigranatumin G (7) exhibited both inhibitory effects on the protein expression of iNOS, COX2, and IL-1β in lipopolysaccharide-stimulated mouse microglia BV2 cells and neuroprotective activity against rotenone-induced injury in mouse midbrain dopaminergic neuron MN9D cells in a dose-dependent manner. Preliminary bioassays indicated that thaigranatumin G might be a valuable lead against neuroinflammation, thus warranting further studies.